PROJECT SUMMARY The proposed program seeks to develop a first-in-class (FIC), peripherally-restricted and long-acting somatostatin receptor type 4 (LA-SSTR4) agonist as a peripheral analgesic for the treatment of moderate-to- severe acute and chronic pain. The program is based on strong scientific evidence showing that activation of peripheral SSTR4 produces broad spectrum analgesic activity. We propose to conjugate existing peptidic SSTR4 agonist pharmacophores to a clinically-validated antibody carrier, previously used successfully to create peripherally-restricted long-acting kappa opioid receptor (LA-KOR) agonists. The resulting peptide-antibody conjugate will retain activity at SSTR4 while acquiring the pharmacokinetic (PK) properties of the antibody carrier, thereby achieving both (i) long elimination half-life and (ii) high peripheral selectivity. These two key features will provide peripherally-restricted LA-SSTR4 agonists with a markedly differentiated and superior target product profile (TPP) in terms of efficacy, safety and convenience compared to short-acting and brain-penetrating small molecule SSTR4 agonists pursued by competitors. The extended half-life will enable less frequent, simpler and more convenient administration, i.e., once weekly (QW) or twice monthly subcutaneous (SC) dosing, that in turn will improve compliance, ensure continuous drug exposure, and ultimately maximize efficacy. The lack of penetration in the central nervous system (CNS) is critical as it will prevent unnecessary and undesired interaction with abundantly expressed SSTR4 in the CNS, thereby eliminating any risk of CNS-mediated SSTR4 side effects. Furthermore, unlike opioids, SSTR4 agonists do not induce constipation, respiratory depression, dependence, addiction or abuse. Finally, SSTR4 expression in the pituitary and pancreas is very low, unlike SSTR2 and SSTR5, suggesting that selective SSTR4 agonists are unlikely to perturb peripheral endocrine functions. This SBIR Phase I proposal is designed to assess the feasibility of creating potent, selective and stable LA-SSTR4 agonists. T he follow up Phase II program will include further lead optimization, evaluation of efficacy, potency and duration of action in acute and chronic pain models, PK studies and selection of a clinical candidate new molecular entity (NME) for preclinical development. IMPACT &